Buprenorphine May Boost HIV Treatment

When patients with HIV infection also are addicted to opioids,treating both disorders simultaneously may help improve outcomesand reduce the spread of HIV or other infections transmittedthrough needle sharing or risky sexual behaviors associatedwith injection drug use. But accessing such integrated carehas sometimes been a challenge for such patients, who generallyhad to seek care for opioid abuse at addiction treatment centersand primary HIV care elsewhere. This could be logistically difficultand often led to delays in receiving care.

Now, however, buprenorphine prescribing by HIV clinicians isoffering patients the option of receiving treatment for bothopioid addiction and HIV infection, an approach that a growingbody evidence indicates benefits individual patients and publichealth.

There are currentlyabout 19 000 US physicians certifiedto prescribe buprenorphine,but experts urge more physicians,particularly those in HIVprimary care, to become certifiedto meet the demand for opioidaddiction treatment.

Since 2002, buprenorphine, a partial opioid agonist, has beenavailable in the United States as an office-based treatmentfor opioid dependence. Physicians who wish to prescribe thedrug may under go a training program and become certified throughthe Substance Abuse and Mental Health Services Administration(SAMHSA) to prescribe buprenorphine (http://buprenorphine.samhsa.gov/).Methadone, a full opioid agonist, remains available throughhighly regulated, specialized treatment programs.

„Buprenorphine has definitely expanded access [to addictioncare],“ said Amina Chaudhry, MD, MPH, an HIV clinician in Baltimorewho prescribes buprenorphine. Chaudhry, who is also a medicalofficer at SAMHSA’s Center for Substance Abuse Treatment inRockville, Md, explained that even in cities like Baltimore,where there may be specialty addiction programs nearby, thedemand for such care often exceeds the available slots. Andrural areas may have no specialty addiction programs at allwithin a reasonable distance.

IMPROVED OUTCOMES

Studies have suggested that patients with HIV infection anduntreated opioid addiction often receive HIV treatment laterin the course of their illness, may be less adherent to theirantiretroviral therapy regimen, and may engage in behaviorssuch as unprotected sex or injection drug use that put themselvesand others at risk of new infections. But treating patientsfor both HIV and drug use can improve such outcomes. Althoughmuch of this research has focused on the effects of methadone,emerging evidence suggests that buprenorphine has similar benefitsand may have a few advantages over methadone treatment for patientswith HIV.

A recent randomized trial found that office-based care can improveaddiction-related outcomes for patients with HIV and opioidaddiction and may lead to faster treatment for addiction (LucasGM et al. Ann Intern Med. 2010;152[11]:704-711). Gregory M.Lucas, MD, PhD, of Johns Hopkins University School of Medicinein Baltimore, and colleagues randomized 93 patients at a BaltimoreHIV clinic to receive buprenorphine therapy at the clinic orto receive a referral to specialty addiction treatment elsewhere.Patients randomized to clinic-based opioid agonist treatmentwith buprenorphine entered addiction treatment much more quickly(84% had initiated such care at 2 weeks compared with 11% inthe referral group). During the 12-month trial, participationin opioid addiction treatment was significantly greater in theclinic-based care group (74% participated in such treatmentvs only 41% in the referral group). Patients receiving buprenorphinein the clinic also had significantly fewer urine test resultsthat were positive for opioids or cocaine and visited theirHIV primary care clinicians more frequently.

However, the researchers did not find differences in HIV-treatmentparticipation or HIV treatment effects between the clinic-basedvs referral groups. The authors concluded that the improvementsin addiction treatment may have been driven by streamlined accessto care because patients referred to outside specialty addictioncare may have experienced a delay in treatment initiation. Thesmall sample size may have precluded identifying clinicallysignificant differences in HIV treatment outcomes, they alsonoted.

The study was part of the Health Resources and Services Administration’s(HRSA’s) Buprenorphine in HIV Primary Care National Evaluationand Support Center (BHIVES; http://www.bhives.org). An analysisof pooled data from 10 sites participating in the HRSA programis under way.

David A. Fiellin, MD, associate professor of medicine at YaleSchool of Medicine and co-investigator on BHIVES, noted thatthe program is also probing which approaches to primary caredelivery work best in HIV clinics. So far, he and his colleagueshave demonstrated in a pilot study that an approach that usesa nurse or other staff member to help coordinate buprenorphinecare by overseeing such tasks as urine testing, drug counseling,and medication monitoring can help to reduce drug use amongHIV patients, has good retention rates, improves patient function,and promotes patient satisfaction (Sullivan LE et al. Clin InfectDis. 2006;43[suppl 4]:S184-S190).

Previous studies had suggested that physicians‘ concerns aboutadherence to antiretroviral treatment by injection drug userswith HIV played a role in the likelihood that such patientswould be offered highly active antiretroviral therapy or atleast experience a delay in receiving such treatment. But resultsof a French study suggest that integrated treatment of HIV andopioid addiction could allay such concerns. The study foundthat retention in opioid substitution therapy, either buprenorphineor methadone, is associated with improved virologic outcomesin patients treated with highly active antiretroviral therapyand who had opioid use disorders (Roux P et al. Clin InfectDis. 2009;49[9]:1433-1440). The study included 53 patients receivingbuprenorphine, 28 receiving methadone, and 32 who were not receivingopioid substitution therapy. The median duration of opioid substitutiontreatment was 25 months.

Buprenorphine also appears to have fewer interactions with antiretroviraldrugs than methadone. Elinore F. McCance-Katz, MD, PhD, professorof psychiatry at the University of California, San Francisco,and her colleagues published an article reviewing drug interactionsinvolving methadone and buprenorphine and other medications,including antiretroviral therapies (McCance-Katz EF et al. AmJ Addict. 2009;19[1]:4-16). Two HIV medications in particular,efavirenz and nevirapine, have been documented to trigger opiatewithdrawal in patients taking methadone but not in patientstaking buprenorphine, despite observations of reduced levelsof both methadone and buprenorphine when these antiretroviralswere given to patients receiving these opioid therapies, notedMcCance-Katz in an interview. A possible reason for the observeddifferences may be that methadone is metabolized to an inactivesubstance while buprenorphine is metabolized to norbuprenorphine,which also has opioid effects and may protect patients fromexperiencing opiate withdrawal, McCance-Katz said.

„It’s very difficult to effectively treat patients [with HIV]if they are in withdrawal,“ she said. „They simply don’t complywith antiretroviral therapy if they are in withdrawal.“

Elevated concentrations of buprenorphine have been documentedin patients with opioid dependence and HIV taking atazanavir;such elevated levels were associated with cognitive impairmentin a few HIV patients in one case study, while another studyin non–HIV-infected patients found only increased drowsiness(Bruce RD and Altice FL. AIDS. 2006;20[5]:783-784 and McCance-KatzEF et al. Drug Alcohol Depend. 2007;91[2-3]:269-278). Such elevationsof methadone concentrations have not been documented with atazanavir.

„In general, buprenorphine has fewer interactions with HIV medications,but neither drug has been looked at extensively with many othermedications,“ she said, adding that many patients with HIV maybe taking a number of medications in addition to antiretroviraldrugs.

Integrating buprenorphine treatment into the HIV care settinghas another potential advantage: it may be easier for cliniciansto spot interactions between addiction and HIV therapies whenpatients receive buprenorphine treatment at their primary HIVclinic, McCance-Katz said. For example, if a patient receivesmethadone at one clinic and antiretroviral therapy at another,there may be limited communication between clinicians at the2 sites and adverse events may not be identified.

CLINICIAN ACCEPTANCE

About 19 000 US physicians are certified to prescribe buprenorphineand about 640 000 patients are receiving the prescriptionscompared with about 4500 certified prescribers and a littlemore than 100 000 patients in 2005, according to NicholasReuter, MPH, senior public health analyst at SAMHSA. But accessto buprenorphine therapy in the HIV primary care setting inthe United States may be limited. Reuter noted that psychiatristsand physicians specializing in addiction treatment were earlyadopters of office-based buprenorphine prescribing. Today, 31%of the prescribers are classified as general or family practitioners,21% as psychiatrists, 15% as internal medicine specialists,and the remaining third are other specialists who are not HIVclinicians, according to Reuter. (SAMHSA doesn’t track the numberof HIV/AIDS specialists who are certified to prescribe buprenorphine.)

A survey of about 500 HIV clinicians (49.7% response rate) whoattended International AIDS Society conferences in the UnitedStates in 2006 found that only 85 (17%) worked in offices thatprescribe buprenorphine. Of the 323 physicians who responded,only 67 (21%) were certified to prescribe the drug, and only19 (6%) had ever done so (Kunins HV et al. Fam Med. 2009;41[10]:722-728).Additionally, when presented with a vignette of an opioid-addictedpatient with HIV, only 16% of the respondents endorsed primarycare buprenorphine treatment as the best option for the patientcompared with 49% who endorsed buprenorphine treatment in asubstance abuse treatment program and 31% who endorsed methadonetreatment in a specialty program.

Fiellin noted that other BHIVES efforts have found that cliniciansmay feel they do not have adequate training and resources toprovide addiction treatment but are interested in receivingadditional training. The clinics that have implemented primarycare buprenorphine care as part of BHIVES have received technicalsupport during implementation, and over time their satisfactionwith and sophistication at providing buprenorphine care haveimproved, he noted.

Another program offering resources to buprenorphine-prescribingphysicians is SAMHSA’s Physician Clinical Support System (PCSS),which is directed by Fiellin and includes McCance-Katz as amongthe clinical experts who work with the program. PCSS helps matchnew buprenorphine prescribers to more experienced mentors whowork in similar settings, including HIV primary care. The programalso has drafted a guidance document for buprenorphine prescribingto patients with HIV (http://www.pcssbuprenorphine.org/pcss/documents2/PCSS_OpioidTherapiesHIVDrugInteractions_022808.pdf).

SAMHSA is also working with primary care physicians at federallyqualified health centers who may be treating many HIV-infectedpatients. Reuter explained that the agency would like thesecenters to offer both buprenorphine and methadone, althoughthe latter would require a center to be licensed as an opioidtreatment clinic. He noted that SAMHSA’s goal is to make surethere are as many physicians as possible qualified to providecare to opioid-dependent patients, who may require long-termor recurrent care. For example, the average duration of methadonetreatment is 6.8 years. „Our concern is that as long as patientsremain engaged in treatment they do very well,“ he said. „Anumber of patients discontinue and the relapse rate is veryhigh.“

Chaudhry emphasized that primary care buprenorphine treatmentis not necessarily a replacement for specialty addiction treatmentwith methadone or buprenorphine. For example, she noted thatsome patients may prefer to keep their addiction treatment separatefrom their HIV care.

„The more treatment choices that providers have to offer thebetter,“ she said.

A Role for Buprenorphine in Prevention?Between 2004 and 2007,of the 152 917 US individuals in 34 states diagnosed withnew HIV infections, 13% of them (n = 19 687)were injection drug users, according to the US Centers for DiseaseControl and Prevention (MMWR Morb Mortal Wkly Rep. 2009;58[46]:1291-1295).For those who are already infected with HIV, buprenorphine treatmentmay reduce the likelihood they will spread the infection toothers through needle sharing or unprotected sexual activity.And for opioid-dependant individuals who are not already HIV-infected,primary care buprenorphine treatment may reduce risky behaviorsthat put them at risk of HIV infection, according to a recentstudy.

Lynn E. Sullivan, MD, and colleagues from the Yale UniversitySchool of Medicine in New Haven, Conn, compared drug-relatedand sex-related risk behaviors in 166 buprenorphine-treatedindividuals at baseline, 12 weeks, and 24 weeks (Sullivan LEet al. J Subst Abuse Treat. 2008;35[1]:87-92). Reports of intravenousdrug use among the individuals declined over time, from 37%at baseline to 12% at 12 weeks, to 7% at 24 weeks. The researchersalso found a decline in reports of sex while the patient ortheir partner was high between baseline (64%) and 12 weeks (13%),although such reports increased to 15% a 24 weeks, and inconsistentcondom use with a regular partner remained unchanged.

Suchbenefits may be particularly important in regions of the worldwhere HIV transmission is driven primarily by injection druguse. In Eastern Europe and Central Asia, for example, the JointUnited Nations Programme on HIV/AIDS estimates that more than80% of all HIV infections are caused by contaminated injectionequipment (http://www.unaids.org/en/PolicyAndPractice/KeyPopulations/InjectDrugUsers/).

TheHIV Prevention Trials Network, an international clinical trialsnetwork funded by the National Institute of Allergy and InfectiousDiseases, currently has a phase 3 randomized trial under wayin China and Thailand to assess whether buprenorphine in combinationwith naloxone (to reduce the abuse potential) decreases druguse and HIV-related risk behaviors (http://www.hptn.org/research_studies/HPTN058.asp).The trial, which is enrolling about 1500 HIV-uninfected injectiondrug users, will randomize individuals to receive either buprenorphineplus naloxone for 1 year or detoxification with buprenorphineplus naloxone for up to 18 days (with a second detoxificationif necessary). Both groups will also receive counseling forHIV risk reduction. The study will assess cumulative HIV incidenceand death and frequency of drug use and drug-related and HIV-relatedrisk behaviors in the 2 groups.—B.M.K.